Identification of AMD3100 (Plerixafor) as a potential lead compound for chlorine toxicity

AMD3100 (Plerixafor) 被鉴定为潜在的氯毒性先导化合物

• 批准号: 10281992
• 负责人: Saurabh Aggarwal
• 金额: $ 44.55万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-21 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10281992
• 关键词: AMD3100; Accidents; Acute; Acute Lung Injury; Adverse effects; Alveolar; Animals; Antineoplastic Agents; Attenuated; Binding; Bleomycin; Blood Circulation; Blood Vessels; Body Weight; Bromine; Bronchoalveolar Lavage Fluid; C57BL/6 Mouse; CXCR4 Receptors; Cells; Cessation of life; Chlorine; Chronic; Clinical; Data; Dose; Endothelial Cells; Epithelial Cells; Exposure to; Extravasation; FDA approved; Fibroblasts; Gases; HIV-1; Heme; Hemolysis; Homing; Hour; Human; Hypoxia; Hypoxia Inducible Factor; Immune; Impairment; In Vitro; Inflammation; Inflammatory; Inhalation; Intramuscular; Irrigation; Irritants; Lead; Leukocytes; Ligands; Lipopolysaccharides; Liquid substance; Literature; Lung; Lung Inflammation; Lymphocyte; Measures; Mediating; Morbidity - disease rate; Mus; Nuclear Translocation; Peripheral; Phosgene; Plants; Plasma; Play; Production; Proteins; Pulmonary Edema; Pulmonary Emphysema; Pulmonary Pathology; Regimen; Regulation; Respiratory Failure; Respiratory Mechanics; Role; Signal Transduction; South Carolina; Structure of parenchyma of lung; Surface; Survivors; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Training; Treatment Efficacy; United States; base; cancer cell; chemokine; dosage; hypoxia inducible factor 1; improved; in vivo; indexing; innovation; leukocyte activation; leukocyte homing; lung injury; macrophage; migration; mortality; neutrophil; novel; nuclear respiratory factor; prevent; seven-transmembrane G-protein-coupled receptor; small molecule; small molecule inhibitor; targeted delivery; water treatment

PROJECT SUMMMARY/ABSTRACT Statement of problem: Chlorine (Cl2) gas is the most common inhalational irritant in the United States, which results in serious adverse effects including lung injury and death. Previous studies by the PI and others have demonstrated that migration and homing of leukocytes (neutrophils and macrophages) into lungs play a critical role in lung morbidity and mortality post Cl2 gas exposure. The binding of the chemokine ligand, stromal- derived-factor-1 (SDF-1), to the C-X-C chemokine receptor type 4 (CXCR4) on lung immune, epithelial, and endothelial cells promote the migration of leukocytes from the circulation to lungs. The SDF-1/CXCR4 axis also propagates the activation and survival of leukocytes in the lungs. Our preliminary data shows that both SDF-1 and CXCR4 levels are elevated in the lungs of Cl2 exposed animals. Therefore, our hypothesis is that SDF- 1/CXCR4 axis is involved in the migration, homing, and survival of leukocytes in lung post exposure to Cl2 and therefore inhibiting this axis by an FDA approved compound, AMD3100 (Plerixafor), would attenuate Cl2- induced lung morbidity and mortality. Specific aims: 1) Establish the role of SDF-1/CXCR4 axis in Cl2-induced lung leukocyte migration, activation, and survival. 2) Optimize the dosage regimen of AMD3100 for Cl2 toxicity. 3) Delineate the mechanisms of SDF-1/CXCR4 regulation post-Cl2 exposure. Experimental approach: C57BL/6 mice will be exposed to Cl2 gas (500ppm, 30min) and then the SDF-1 concentration in broncholaveolar lavage fluid and the CXCR4 surface expression on the alveolar leukocytes and whole lung tissue will be measured over time. It will also be analyzed whether, the SDF-1/CXCR4 axis mediates Cl2 dependent migration, activation, and survival of lung leukocytes. Next the Cl2 exposed mice will be administered a clinically safe dose (0.01-0.16 mg/kg) of AMD3100 intramuscularly and the indices of acute and chronic lung injury and mortality will be measured. Finally, the role of Cl2-induced hemolysis and hypoxia in the regulation of lung SDF-1 and CXCR4 levels post Cl2 exposure will be studied in vitro and in vivo. Anticipated results: We anticipate that AMD3100 will attenuate leukocyte translocation to lungs and subsequently mitigate lung injury and improve survival in mice exposed to Cl2. Innovation: The study is the first to propose the use of a novel, FDA-approved, small molecule compound, AMD3100, to mitigate lung injury and mortality post exposure to Cl2 gas. AMD3100 may be beneficial in mitigating lung injury post exposure to other toxic gases such as bromine and phosgene, which are also associated with hemolysis and increased migration of leukocytes into lung.

项目SUMMMARY /文摘